Zolpimist

"The U.S. Food and Drug Administration today announced it is requiring the manufacturers of Ambien, Ambien CR, Edluar and Zolpimist, widely used sleep drugs that contain the active ingredient zolpidem, to lower current recommended doses. Ambi"...

Zolpimist

CLINICAL PHARMACOLOGY

Mechanism of action

Zolpidem, the active moiety of zolpidem tartrate, is a hypnotic agent with
a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs
with known hypnotic properties. It interacts with a GABA-BZ receptor complex
and shares some of the pharmacological properties of the benzodiazepines. In
contrast to the benzodiazepines which non-selectively bind to and activate all
BZ receptor subtypes, zolpidem in vitro binds the BZ1 receptor preferentially
with a high affinity ratio of the α1/α5 subunits.
This selective binding of zolpidem on the BZ1 receptor is not absolute,
but it may explain the relative absence of myorelaxant and anticonvulsant effects
in animal studies as well as the preservation of deep sleep (stages 3 and 4)
in human studies of zolpidem at hypnotic doses.

Pharmacokinetics

Zolpimist (zolpidem tartrate) Oral Spray is bioequivalent to Ambien® tablets
(Sanofi-Aventis). The pharmacokinetic profile of Zolpimist (zolpidem tartrate oral spray) is characterized
by rapid absorption from the oral mucosa and gastrointestinal tract, and a short
t½ in healthy subjects.

In a single-dose crossover study in 10 healthy young (18-40 years of age) male
subjects administered 2.5, 5, and 10 mg Zolpimist (zolpidem tartrate oral spray) , the results demonstrated
a linear relationship to dose for mean Cmax and AUC0-∞ over
the range of doses administered in the study.

In a single-dose crossover study in 43 healthy young (18-45 years of age) subjects
administered 5 and 10 mg Zolpimist (zolpidem tartrate oral spray) , the means for Cmax were 114 (range: 19 to
197) and 210 ng/mL (range: 77 to 401), respectively, occurring at a mean Tmax
of approximately 0.9 hours for both. The mean zolpidem t½ was 2.7 (range:
1.7 to 5.0) and 3.0 hours (range: 1.7 to 8.4), for 5 and 10 mg Zolpimist (zolpidem tartrate oral spray) , respectively.
In the same study, the means for Cmax were 123 (range: 53 to 221) and 219 ng/mL
(range: 101 to 446) for 5 and 10 mg Ambien® tablets, respectively, occurring
at a mean Tmax of 0.9 and 1.0 hours, respectively. The mean zolpidem t½
was 2.8 (range: 1.5 to 6.0) and 3.1 hours (range: 1.1 to 8.6) for the 5 and
10 mg Ambien® tablets, respectively.

Zolpidem is converted to inactive metabolites that are eliminated primarily
by renal excretion. Total protein binding for zolpidem was found to be 92.5
± 0.1% and remained constant, independent of concentration between 40
and 790 ng/mL. Zolpidem did not accumulate in young adults following nightly
dosing with 20 mg zolpidem tartrate for 2 weeks.

A food-effect crossover study in 14 healthy young (18-45 years of age) male
subjects compared the pharmacokinetics of Zolpimist (zolpidem tartrate oral spray) 10 mg when administered
while fasting at least 8 hours or 5 minutes after eating a standard high-fat
meal. Results demonstrated that with food, mean AUC0-∞ and Cmax were decreased
by 27% and 58%, respectively, while mean Tmax was prolonged by 225% (from 0.8
to 2.6 hours). These results suggest that, for faster sleep onset, as with all
zolpidem products, Zolpimist (zolpidem tartrate oral spray) should not be administered with or immediately
after a meal.

Special Populations

Elderly: In the elderly, the dose for zolpidem tartrate should
be 5 mg [see WARNINGS AND PRECAUTIONS and
DOSAGE AND ADMINISTRATION]. This recommendation
is based on several studies in which the mean Cmax, t½, and AUC were
significantly increased when compared to results in young adults administered
zolpidem tartrate. In a pharmacokinetic study of 24 elderly ( ≥ 65 years
of age) subjects administered 5 mg Zolpimist (zolpidem tartrate oral spray) , the means for Cmax and AUC were
134 ng/mL and 493 ng*hr/mL respectively, following administration of a single
5 mg oral dose of Zolpimist. Zolpidem tartrate did not accumulate in elderly
subjects following nightly oral dosing of 10 mg for 1 week.

Hepatic Impairment: The pharmacokinetics of zolpidem in eight
patients with chronic hepatic insufficiency were compared to results in healthy
subjects. Following a single 20 mg oral zolpidem tartrate dose, mean Cmax and
AUC were found to be two times (250 vs 499 ng/mL) and five times (788 vs 4,203
ng*hr/mL) higher, respectively, in hepatically compromised patients. Tmax did
not change. The mean t½ in cirrhotic patients of 9.9 hours (range: 4.1
to 25.8 hours) was greater than that observed in normal subjects of 2.2 hours
(range: 1.6 to 2.4 hours). Dosing should be modified accordingly in patients
with hepatic insufficiency [see DOSAGE AND ADMINISTRATIONand WARNINGS AND PRECAUTIONS].

Renal Impairment: The pharmacokinetics of zolpidem were studied
in 11 patients with endstage renal failure (mean ClCr = 6.5 ±
1.5 mL/min) undergoing hemodialysis three times a week, who were dosed with
zolpidem tartrate 10 mg orally each day for 14 or 21 days. No statistically
significant differences were observed for Cmax, Tmax, t½, and AUC between
the first and last day of drug administration when baseline concentration adjustments
were made. On Day 1, Cmax was 172 ± 29 ng/mL (range: 46 to 344 ng/mL).
After repeated dosing for 14 or 21 days, Cmax was 203 ± 32 ng/mL (range:
28 to 316 ng/mL). On Day 1, Tmax was 1.7 ± 0.3 hours (range: 0.5 to 3.0
hours); after repeated dosing Tmax was 0.8 ± 0.2 hour (range: 0.5 to
2.0 hours). This variation is accounted for by noting that last-day serum sampling
began 10 hours after the previous dose, rather than after 24 hours. This resulted
in residual drug concentration and a shorter period to reach maximal serum concentration.
On Day 1, t½ was 2.4 ± 0.4 hours (range: 0.4 to 5.1 hours). After
repeated dosing, t½ was 2.5 ± 0.4 hours (range: 0.7 to 4.2 hours).
AUC was 796 ± 159 ng*hr/mL after the first dose and 818 ± 170
ng*hr/mL after repeated dosing. Zolpidem was not hemodialyzable. No accumulation
of unchanged drug appeared after 14 or 21 days. Zolpidem pharmacokinetics were
not significantly different in renally impaired patients.

No dosage adjustment is necessary in patients with compromised renal function.
However, as a general precaution, these patients should be closely monitored.

Clinical Studies

Transient insomnia

Normal adults experiencing transient insomnia (n=462) during the first night
in a sleep laboratory were evaluated in a double-blind, parallel group, single-night
trial comparing two doses of zolpidem (7.5 and 10 mg) and placebo. Both zolpidem
doses were superior to placebo on objective (polysomnographic) measures of sleep
latency, sleep duration, and number of awakenings.

Normal elderly adults (mean age 68) experiencing transient insomnia (n=35)
during the first two nights in a sleep laboratory were evaluated in a double-blind,
crossover, 2-night trial comparing four doses of zolpidem (5, 10, 15, and 20
mg) and placebo. All zolpidem doses were superior to placebo on the two primary
PSG parameters (sleep latency and efficiency) and all four subjective outcome
measures (sleep duration, sleep latency, number of awakenings, and sleep quality).

Chronic insomnia

Zolpidem was evaluated in two controlled studies for the treatment of patients
with chronic insomnia (most closely resembling primary insomnia, as defined
in the APA Diagnostic and Statistical Manual of Mental Disorders, DSM-IV™).
Adult outpatients with chronic insomnia (n=75) were evaluated in a double-blind,
parallel group, 5-week trial comparing two doses of zolpidem tartrate and placebo.
On objective (polysomnographic) measures of sleep latency and sleep efficiency,
zolpidem 10 mg was superior to placebo on sleep latency for the first 4 weeks
and on sleep efficiency for weeks 2 and 4. Zolpidem was comparable to placebo
on number of awakenings at both doses studied.

Adult outpatients (n=141) with chronic insomnia were also evaluated, in a double-blind,
parallel group, 4-week trial comparing two doses of zolpidem and placebo. Zolpidem
10 mg was superior to placebo on a subjective measure of sleep latency for all
4 weeks, and on subjective measures of total sleep time, number of awakenings,
and sleep quality for the first treatment week.

Increased wakefulness during the last third of the night as measured by polysomnography
has not been observed in clinical trials with zolpidem.

Studies pertinent to safety concerns for sedative-hypnotic drugs

Next-day residual effects: Next-day residual effects of zolpidem
tartrate were evaluated in seven studies involving normal subjects. In three
studies in adults (including one study in a phase advance model of transient
insomnia) and in one study in elderly subjects, a small but statistically significant
decrease in performance was observed in the Digit Symbol Substitution Test (DSST)
when compared to placebo. Studies of zolpidem tartrate in non-elderly patients
with insomnia did not detect evidence of next-day residual effects using the
DSST, the Multiple Sleep Latency Test (MSLT), and patient ratings of alertness.

Rebound effects: There was no objective (polysomnographic) evidence
of rebound insomnia at recommended doses seen in studies evaluating sleep on
the nights following discontinuation of zolpidem tartrate. There was subjective
evidence of impaired sleep in the elderly on the first post-treatment night
at doses above the recommended elderly dose of 5 mg.

Memory impairment: Controlled studies in adults utilizing objective
measures of memory yielded no consistent evidence of next-day memory impairment
following the administration of zolpidem tartrate. However, in one study involving
zolpidem doses of 10 and 20 mg, there was a significant decrease in next-morning
recall of information presented to subjects during peak drug effect (90 minutes
post-dose) (i.e., these subjects experienced anterograde amnesia). There was
also subjective evidence from adverse event data for anterogradeamnesia occurring
in association with the administration of zolpidem tartrate, predominantly at
doses above 10 mg.

Effects on sleep stages: In studies that measured the percentage
of sleep time spent in each sleep stage, zolpidem tartrate has generally been
shown to preserve sleep stages. Sleep time spent in stages 3 and 4 (deep sleep)
was found comparable to placebo with only inconsistent, minor changes in REM
(paradoxical) sleep at the recommended dose.

Last reviewed on RxList: 2/23/2009
This monograph has been modified to include the generic and brand name in many instances.